This is a renewal grant application for an ongoing clinical trial whose primary objective is to establish whether bilateral transplantation of fetal mesencephalic allografts into the post- commissural putamen can safely improve the signs and symptoms of advanced Parkinson's disease (PD) and alter the rate of progression of disability in patients with this disorder. The study is a prospective, randomized, double-blind 2 year trial comparing fetal nigral transplantation with 1 or 4 donors per side to a cosmetic placebo operation in 36 patients. The study is designed to provide information on the safety and efficacy of fetal nigral transplantation in PD as well as to assess whether benefits are influenced by the number of donor embryos implanted. As clinical outcomes we have employed motor function during "on and off" stages, percent "on and off" time during the waking day, activity of daily living scores, a quality of life instrument, and neuropsychologic measures of cognitive function. Striatal fluorodopa (FD) uptake on position emission tomography (PET) has been used as a measure of putative graft viability. During the previous funding period (3 years) we have enrolled 31 patients and identified 5 candidates who are presently undergoing screening. Eleven patients have completed the study. There have been no drop outs and no deaths. As preliminary data, we performed an opn label trial of fetal nigral transplantation in 6 patients using transplant variables virtually identical to the ones employed in the present study (1-3). These patients have shown significant improvement in motor function and a progressive increase in striatal FD uptake on PET which has persisted for a mean of 20.5 months. Two patients who participated in our open label trial expired 18 months after the transplant procedure from unrelated causes. Post-mortem studies demonstrated robust survival of implanted dopaminergic neurons with extensive reinnervation of the striatum in an organotypic fashion (4-6). These landmark studies provide the first demonstration that implanted fetal nigral cells can survive and reinnervate the striatum in PD patients. This renewal grant will enable us to complete the present clinical trial, perform an extension study, and perform post-mortem neuroanatomic and molecular studies to characterize grafted and host nigral neurons in these unique tissues.